Inhibitors of HIV Nucleocapsid Protein Zinc Fingers as Candidates for the Treatment of AIDS

• Published in: Science (American Association for the Advancement of Science) Vol. 270; no. 5239; pp. 1194 - 1197
• Main Authors: Rice, William G., Supko, Jeffrey G., Malspeis, Louis, Buckheit, Robert W., Clanton, David, Bu, Ming, Graham, Lisa, Schaeffer, Catherine A., Turpin, Jim A., Domagala, John, Gogliotti, Rocco, Bader, John P., Halliday, Susan M., Coren, Lori, Sowder, Raymond C., Arthur, Larry O., Henderson, Louis E.
• Format: Journal Article
• Language: English
• Published: Washington, DC American Society for the Advancement of Science 17.11.1995; American Association for the Advancement of Science; The American Association for the Advancement of Science
• Subjects: AIDS; AIDS (Disease); Amino Acid Sequence; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - chemistry; Antiviral Agents - pharmacokinetics; Antiviral Agents - pharmacology; Antivirals; Benzamides - chemistry; Benzamides - pharmacokinetics; Benzamides - pharmacology; Biological and medical sciences; Biological Availability; Capsid - chemistry; Capsid - metabolism; Capsid Proteins; Cell Line; Disulfides - chemistry; Disulfides - pharmacokinetics; Disulfides - pharmacology; Dosage; Drug resistance; Drug Resistance, Microbial; Drug Synergism; Drug therapy; Fingers; gag Gene Products, Human Immunodeficiency Virus; Gene Products, gag - antagonists & inhibitors; Gene Products, gag - chemistry; HIV 1; HIV-1 - drug effects; HIV-1 - physiology; human immunodeficiency virus 1; Humans; Infections; Male; Medical sciences; Mice; Molecular Sequence Data; Nucleocapsid proteins; Pharmacology. Drug treatments; Viral Proteins; Virions; Viruses; Zinc; Zinc Fingers - drug effects; Immunopathology; HIV-1 virus; Zinc finger structure; Nucleocapsid; Retroviridae; AIDS; Immune deficiency; Biological activity; Infection; Virus; Proteins; Chemotherapy; Treatment; Viral disease; Lentivirinae; Antiviral; Inhibitor; Human immunodeficiency virus
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.270.5239.1194

Strategies for the treatment of human immunodeficiency virus-type 1 (HIV-1) infection must contend with the obstacle of drug resistance. HIV-1 nucleocapsid protein zinc fingers are prime antiviral targets because they are mutationally intolerant and are required both for acute infection and virion assembly. Nontoxic disulfide-substituted benzamides were identified that attack the zinc fingers, inactivate cell-free virions, inhibit acute and chronic infections, and exhibit broad antiretroviral activity. The compounds were highly synergistic with other antiviral agents, and resistant mutants have not been detected. Zinc finger-reactive compounds may offer an anti-HIV strategy that restricts drug-resistance development.